The mouse carcinogenicity study is no longer a scientifically justifiable core data requirement for the safety assessment of pesticides

Abstract

Regulatory tests investigating pesticide carcinogenicity potential routinely comprise a battery of in vitro and in vivo genotoxicity studies and two cancer bioassays, one in rats and one in mice. The genotoxicity testing strategy essentially ensures that genotoxic compounds are eliminated, and any carcinogens identified in subsequent lifetime studies are probably nongenotoxic in character. Assessment of 202 pesticide evaluations from the European Union review programme under Directive 91/414/EEC indicated that the mouse carcinogenicity study contributed little or nothing to either derivation of an acceptable daily intake (ADI) for assessment of chronic risk to humans, or hazard classification for labelling purposes. From a pesticide approval perspective, the mouse study did not influence a single outcome. From a risk assessment perspective, the ADI for just one pesticide was based on tumours in mice and this would have barely changed if the mouse data had not been available. In total, only 10 (5%) pesticide ADIs were based solely on the mouse carcinogenicity study and even in these few cases, a similar value would have been identified from other studies if the mouse study had not been available. For pesticides with treatment-related tumours only in mice, just three, or 1.5%, were classified as carcinogens and all were in the lowest category, Category 3 (R40). For pesticides with treatment-related tumours in mice and rats, the mouse data were probably the main, if not the only, cause for another three cases of R40 classification. Absence of the mouse studies would not have influenced assignment of the higher, Category 2 (R45), cancer classification for any substance with treatment-related tumours in both species as all decisions for these substances were limited to Category 3 or ‘unclassified’ outcomes. Over 100,000 mice were used to test these pesticides. This review shows that the mouse carcinogenicity studies did not provide significant information over and above that provided by the rat studies, and underpins the opportunity, from both a scientific and an animal welfare perspective, to remove the mouse carcinogenicity study from regulatory data requirements for the testing of pesticides.

Keywords::

• Animal use (3Rs)
• carcinogenicity studies
• hazard classification
• mouse
• pesticides
• risk assessment

Acknowledgements

The authors gratefully acknowledge the assistance of Gaynor Cleisham for technical editing, numerous colleagues in various companies for their help and review of specific information on their company’s molecules, Dr. Bhaskar Gollapudi for technical review of the initial manuscript, and Peter Watts and James Hopkins of BIBRA–Toxicology Advice & Consulting (TAC) for review of the final manuscript.

Declaration of interest

The preparation of this review was conducted as part of the normal work of the authors, whose employment affiliation is shown on the first page of this review. Dow AgroSciences and Syngenta Crop Protection are private companies that develop, manufacture, and market pesticide products and thus routinely use the studies discussed in this review as part of regulatory safety assessment procedures. The Chemicals Regulation Directorate (CRD) is a directorate of the UK Health & Safety Executive (HSE). One of the primary aims of CRD is to ensure the safety of pesticides to humans and the environment. The authors alone are responsible for the content and writing of the paper. The views expressed in this article are those of the authors and are not necessarily those of their employers and do not necessarily reflect the views or policies of the Chemicals Regulation Directorate or other institutions represented by the authors. The contents and conclusions drawn in the paper are intended to challenge the way toxicology data used in the safety assessments of pesticides are generated and help reduce the unnecessary use of animals in this field.

Notes

¹Replacement, refinement, and reduction: http://www.nc3rs.org.uk/page.asp?id=7.

²International Life Sciences Institute–Health and Environmental Sciences Institute.